Background: Spirometry with bronchodilator testing (BDT) is used routinely in the diagnosis and clinical phenotyping of obstructive lung diseases.Previous reports (1) have demonstrated that individuals with FEV 1 > 90% predicted are unlikely (0 -1.9%) to meet ATS/ERS criteria (2) for bronchodilator response (BDR) and suggest that BDT is not clinically useful in such patients.However, that study was performed in patients with all types of suspected lung disease and we examined whether criteria to limit BDT using baseline FEV 1 would be applicable in patients with self-reported asthma.Methods: A retrospective observational study of adult patients with self-reported asthma at a single center in Boston, MA between 1997 and 2020.Spirometry testing was performed in accordance with ATS guidelines for acceptability and repeatability on subjects in the seated position using nose clips and all subjects were given a total of 360μg of albuterol in 4 separate doses and spirometry was repeated 15-30 minutes later.All subjects withheld underlying medications as per ATS guidelines.We grouped BDR by decile of predicted FEV 1 .We used the Mantel-Haenszel Chi-square test to assess the significance of reversibility across decile of FEV 1 .Results: A total of 1,941 individuals with complete pre-and post-bronchodilator data were analyzed.The mean age was 38 ± 14.5 and 66% (n = 1276) were female.The mean baseline FEV 1 was 80% + 24.A total of 535 (28%) showed a positive BDR, and overall men were more likely to have a positive BDR (33% vs 25% for men and women, respectively; p < 0.001).There was a stepwise decrease in the frequency of reversibility with increasing decile of baseline predicted FEV 1 (p < 0.001; Figure 1).All subjects (n = 8) with a BDR and baseline FEV 1 > 100% predicted were female (p = 0.2).There were no significant differences in the frequency of reversibility for individuals with as needed reliever or asthma controller therapies (all p > 0.05).Discussion: Whereas previous studies have suggested that BDT in patients with an FEV 1 > 90% predicted might not be clinically useful, we found that 15% of patients with an FEV 1 > 90% with a self-report of asthma demonstrated BDR.Men are overall more likely to have reversibility compared to women.There was no relationship between asthma controller therapy and probability of reversibility.These data suggest that BDT may still be useful in confirming asthma even in patients with high baseline FEV 1 .

Obstructive sleep apnea (OSA), although a growing healthcare problem and documented risk factor for cardiovascular diseases, is still under-diagnosed in cardiac patients. To investigate the correlation between OSA and echocardiographic parameters of right ventricle diastolic (RVD) dysfunction, in particular trans-tricuspid E-wave deceleration time (EDT), we retrospectively analyzed data of 103 pure (comorbidity-free) OSA patients with comprehensive echocardiographic examination (ETT). Apnea/hypopnea index (AHI), oxygen desaturation index (ODI), mean nighttime oxyhemoglobin saturation (SpO2), time elapsed with SpO2 < 90% (T90) and mean peak desaturation of nocturnal events (Mdes, graded as mild, medium or severe) were compared with echocardiographic parameters. We found RVD dysfunction present in 58.3% of patients. Altered EDT correlated significantly with mean SpO2, T90, and Mdes (p < 0.01, all). Nocturnal desaturators had a significantly worse EDT than non-desaturators (p = 0.027) and a higher risk of prolonged EDT (odds ratio, OR = 2.86). EDT differed significantly according to Mdes severity (p = 0.005) with a higher risk of prolonged EDT in medium/severe vs. mild Mdes (OR = 3.44). EDT detected the presence of RVD dysfunction in 58.3% of our pure OSA patients. It correlated poorly with AHI severity but strongly with nocturnal desaturation severity, independently of age. This ETT marker may be useful for deciding appropriate diagnostic and therapeutic strategies.

OBJECTIVE:In rheumatoid arthritis (RA) the synovial membrane proliferates and invades the underlying tissues. The cell-associated fibrinolytic system (urokinase-type plasminogen activator, uPA; uPA receptor, uPAR; plasminogen activator inhibitor-type 1, PAI-1) is pivotal in cell invasion and proliferation. For this reason, the expression and the role of such enzymatic system was investigated in synovial fibroblasts (SF) of normal and RA patients.METHODS:In SF obtained from RA patients and control subjects, uPA, uPAR and PAI-1 were measured by ELISA of cell lysates and culture medium and by RT-PCR of mRNAs. uPA was also studied by zymography. Proliferation was measured by cell counting and cell invasion with the Boyden chamber.RESULTS:RA-SF over-express uPAR and PAI-1 and are more prone than the normal counterpart to spontaneous and uPA-challenged invasion and proliferation, which are counteracted by antagonists of the fibrinolytic system.CONCLUSIONS:RA-SF display the fibrinolytic pattern and behaviour of invasive tumor-like cells. Antagonists of the fibrinolytic system are able to revert growth and invasion of both normal and RA-SF.

The present study demonstrates that stimulation of hormonal receptors of proximal tubule cells with the serotonin‐agonist 8‐hydroxy‐2‐(di‐n‐propylamino) tetraline (8‐OH‐DPAT) induces an augmentation of Na+,K+‐ATPase activity that results from the recruitment of enzyme molecules to the plasmalemma. Cells expressing the rodent wild‐type Na+,K+‐ATPase α‐subunit had the same basal Na+,K+‐ATPase activity as cells expressing the α‐subunit S11A or S18A mutants, but stimulation of Na+,K+‐ATPase activity was completely abolished in either mutant. 8‐OH‐DPAT treatment of OK cells led to PKCβ‐dependent phosphorylation of the α‐subunit Ser‐11 and Ser‐18 residues, and determination of enzyme activity with the S11A and S18A mutants indicated that both residues are essential for the agonist‐dependent stimulation of Na+,K+‐ATPase activity. When cells were treated with both dopamine and 8‐OH‐DPAT, an activation of Na+,K+‐ATPase was observed at basal intracellular sodium concentration (∼9 mM), and this activation was gradually reduced and became a significant inhibition as the concentration of intracellular sodium gradually increased from 9 to 19 mM. Thus, besides the antagonistic effects of dopamine and 8‐OH‐DPAT, intracellular sodium modulates whether an activation or an inhibition of Na+,K+‐ATPase is produced. British Journal of Pharmacology (2002) 137, 1380–1386. doi:10.1038/sj.bjp.0704962

Background Previous studies have shown that molecular variants of the cytoskeletal protein adducin may be involved in regulation of blood pressure both in genetic rat hypertension and in human essential hypertension.Objective To investigate the relationship of genetic polymorphism of a-adducin with blood pressure, cardiovascular structure, and some biochemical indexes of cardiovascular risk in a sample of general population.Design and methods A sample of 246 subjects (124 men and 122 women, aged 57.7 +/- 3.7 years) was randomly chosen from a middle-aged population. Twenty-four-hour ambulatory blood pressure, as well as left ventricular mass (by echocardiographic methods) and carotid wall thickness (by B-mode ultrasound methods) were measured. DNA was extracted from peripheral blood samples; the Gly460Trp diallelic variant of human a-adducin was genotyped by polymerase chain reaction amplification and then allele-specific oligo hybridization.Results A trend toward higher 24 h ambulatory blood pressure values in subjects not treated with antihypertensive drugs was observed among carriers of Trp460 allele, although the differences did not attain statistical significance (at closest, P = 0.066 for a dominant effect of Trp460 on systolic blood pressure). When blood pressure was considered a dichotomous variable, allowing the inclusion of treated hypertensives), a higher prevalence of Trp460 allele among hypertensives was observed (0.188 versus 0.106 among normotensives, P = 0.02). There was no evidence of association either of left ventricular mass or of common carotid wall thickness with Gly460Trp polymorphism.Conclusions In this sample of a general population, the relationship of a genetic polymorphism of a-adducin with blood pressure values was rather weak. However, a population-based case-control analysis indicated that there was an association between Trp460 allele and hypertension, with a relative risk for subjects carrying at least one Trp460 allele of approximately 1.6. Further investigation of larger and different population samples in order to assess the role of adducin gene polymorphism as a marker of genetic predisposition to the development of hypertension is warranted. (C) Rapid Science Publishers ISSN 0263-6352.

In Caucasian hypertensives and diabetics, increased RBC sodium-lithium countertransporter activity (V ) is a metabolic marker for end-organ complications.~fihough V~.l is decreased in African-Americans compared to Caucasians, a subgroup of African-Americans with increased V.w show strong correlations with d slipidemia, insulin resistance, J microalbuminuria and bloo pressure.The purpose of our study was to determine if V~in premenopausal African-American women correlates w%! Iefl ventricular hypertrophy (LVH) before the onset of clinically diagnosed hypertension.METHODS: Normotensive, non-diabetic African-American women (N=21 ,ages 28-38) underwent anthropometric and blood pressure measurements, oral glucose tolerance test (OGTT), euglycemic hyperinsulinemic clamp, fasting lipid profile in the follicular phase of the menstrual cycle, RBC SLC assa (VA and 2-D echocardiography.Left ventricular mass (LV~) was calculated by the cube root formula and adjusted for height (LVM/ht).RESULTS: V~was strongly correlated ,withaverage systolic blood ressure~R=.53,P=.007), the sum of insulin during the OG?T (R=.55,P=.006),and insulin sensitivity adjusted for fat free mass (M'), ( R=-.69, P=.000).LVM/ht was not a statistically significant correlate of V~( R=.24,P=.146)or posterior wall thickness (R=.33,P=.071).LVM/ht strongly correlated with average systolic blood pressure (R=.44,P=.022),sum of insulin in the OGTT (R=.41,P=.037),and insulin sensitivity during the clamp (M') (R=-.38,P=.O48).CONCLUSIONS: V~,J is associated with insulin sensitivity and insulin resistance m a small sample of normotensive, non-diabetic African-American women.Although the correlation analysis did not reach statistical si nificanca in this small sample, V ,x may be associated with Ĩe ventricular wall thickness

The aim of this study was to evaluate the delayed effects of an angiotensin converting enzyme (ACE) inhibitor on blood pressure and on structural and functional alterations in mesenteric small resistance arteries of spontaneously hypertensive rats (SHR). The ACE inhibitor fosinopril (25 mg/kg/day) was administered according to three different schedules: in one group of SHR from 4 to 8 weeks of age (n = 12), in a second group from 8 to 12 weeks of age (n = 15), and in a third group from 4 to 12 weeks of age (n = 12). Eighteen untreated SHR and 18 untreated Wistar-Kyoto rats served as controls. About half the animals in each group were killed at 13 weeks of age, and the remaining were killed at 38 weeks of age. After death, relative left ventricular mass (left ventricular weight/body weight) was calculated. Vascular morphology (media : lumen ratio) and function (responses to norepinephrine and acetylcholine) in mesenteric small resistance arteries were then assessed using a micromyographic technique.

The aims of this study were to determine the prevalence of structural changes in the carotid arteries and heart and the correlation between these changes and the commonly recognized cardiovascular risk factors in the general population. Structural changes in the carotid arteries were defined as the intima-media thickness of the artery measured by B-mode ultrasound. Changes in the heart were defined as left ventricular mass index (LVMI) measured by echocardiography. LVMI values greater than 134 g/m2 in men and greater than 110 g/m2 in women were considered abnormal, indicating the presence of left ventricular hypertrophy. Blood pressure (BP) was measured in the clinic setting with a mercury sphygmomanometer and by 24-hour noninvasive ambulatory monitoring. Hypertension was defined as a sustained systolic BP greater than or equal to 160 mm Hg and/or diastolic BP increase greater than or equal to 95 mm Hg. The study population consisted of 225 subjects (107 women and 118 men) 48 to 64 years old. Prevalence of intima-media thickening (intima-media thickness > 1 mm) was 11% in normotensive subjects and 44% in hypertensive subjects. The presence of plaque (wall thickening with either mineralization or focal protrusion in the lumen at least 50% greater than the surrounding wall, usually > 2 mm) was observed in 35% of normotensive subjects and 44% of hypertensive subjects. The prevalence of left ventricular hypertrophy was 13% in normotensive subjects and 19% in hypertensive subjects. Intima-media thickness in the common and bifurcation segments of carotid arteries correlated well with LVMI (r = .20 and r = .19, respectively; P < .01). Intima-media thickness and LVMI were both positively related to 24-hour monitored BP (P < .01). However, in the multivariate analysis, body mass index (P = .027), sex (P < .001), and 24-hour mean BP (P = .025) were the most significant determinants of LVMI, whereas carotid artery intima-media thickness was found to be associated best with age (P < .001), cigarette smoking (P = .009), serum cholesterol (P = .025), serum glucose (P = .038), and nighttime systolic BP (P = .006). Logistic regression analysis confirmed the association between the presence of plaque and age (P < .001), nighttime systolic BP (P < .05), and cigarette smoking (P < .05); a negative association between plaque and the decrease in mean systolic BP daytime to nighttime was also observed (P < .001). In conclusion, in a general population of unselected middle-aged subjects, carotid wall thickness and LVMI were associated with each other and related to 24-hour BP levels although the major determinants of carotid wall and cardiac structure were different.

OBJECTIVE:Left ventricular hypertrophy (LVH) and depressed left ventricular performance have been shown to be associated to an adverse prognosis in hypertensive patients. It has not been established, however, whether, during chronic antihypertensive treatment, the increased cardiovascular risk is more strictly related to the presence of LVH or of a low left ventricular performance.DESIGN AND METHODS:A total of 215 patients with uncomplicated hypertension (129 males, 86 females; age range 18-70 years, mean +/- SD 45 +/- 11) underwent an echocardiographic evaluation of left ventricular anatomy and function. In 151 patients (87 males, 64 females; age range 18-70 years, mean 45 +/- 10.4) the echocardiogram was repeated on average 10 +/- 1 years after the initial study. The presence of LVH (left ventricular mass index > 134 g/m2 in males and 110 g/m2 in females) and the midwall left ventricular shortening/end-systolic stress relationship were prospectively analysed as predictors of cardiovascular non-fatal events (n = 23) in patients who were seen at follow-up.RESULTS:The incidence of non-fatal cardiovascular events was greater in patients with LVH (n = 17, P < 0.0001) and in those with a lower midwall performance (n = 14, P < 0.01) at baseline. At follow-up, the incidence of non-fatal cardiovascular events was significantly greater in patients without a reduction in the left ventricular mass index, after adjusting for traditional risk factors (relative risk 3.52 versus 1.38 in patients with persistence and regression of LVH, respectively; P < 0.01). The baseline midwall fractional shortening was lower in patients with both persistence or regression of LVH (analysis of variance, P < 0.0001) than in patients with a normal left ventricular mass index. In logistic analysis, the left ventricular mass index at follow-up and age were independent determinants of non-fatal cardiovascular events (P < 0.001); without the left ventricular mass index at follow-up, this analysis showed that age, systolic blood pressure at follow-up and baseline midwall fractional shortening were independent determinants of non-fatal cardiovascular events.CONCLUSIONS:Our results suggest that lack of regression of LVH is a stronger indicator of cardiovascular risk than a depressed baseline midwall left ventricular performance.

The angiotensin II type 1 (AT 1 ) receptor has a key role in mediating the vasoconstrictor and growth-promoting effects of angiotensin II. It has been reported that a polymorphism of the AT 1 receptor gene (an A/C transversion at position 1166) may be associated with cardiovascular phenotypes, such as arterial blood pressure and aortic stiffness, that underlie a condition of increased cardiovascular risk. We examined a sample of 212 subjects randomly selected from a general population in northern Italy to investigate the role of AT 1 receptor gene polymorphism in the regulation of blood pressure and cardiovascular growth. We measured blood pressure (both clinic and 24-hour ambulatory recording), left ventricular mass (echocardiography), and carotid artery wall thickness (B-mode ultrasound); we assessed the AT 1 receptor genotype by polymerase chain reaction and allele-specific oligonucleotide hybridization. Blood pressure values were lower in CC homozygotes than in heterozygotes and AA homozygotes; the difference was statistically significant for clinic measurements (mean difference for mean blood pressure, −6.6 mm Hg, P =.01; 95% confidence interval, −1.6 to −11.7 mm Hg) but not for ambulatory blood pressure measurements. CC homozygotes also presented a lower incidence of a positive family history of hypertension ( P =.027). No statistically significant differences among AT 1 receptor A/C 1166 genotypes were observed for left ventricular mass or carotid artery wall thickness. We conclude that the present study does not support a major role of the AT 1 receptor gene A/C 1166 polymorphism as a marker of conditions associated with increased cardiovascular risk.

The angiotensin II type 1 (AT1) receptor has a key role in mediating the vasoconstrictor and growth-promoting effects of angiotensin II. It has been reported that a polymorphism of the AT1 receptor gene (an A/C transversion at position 1166) may be associated with cardiovascular phenotypes, such as arterial blood pressure and aortic stiffness, that underlie a condition of increased cardiovascular risk. We examined a sample of 212 subjects randomly selected from a general population in northern Italy to investigate the role of AT1 receptor gene polymorphism, in the regulation of blood pressure and cardiovascular growth. We measured blood pressure (both clinic and 24-hour ambulatory recording), left ventricular mass (echocardiography), and carotid artery wall thickness (B-mode ultrasound); we assessed the AT1 receptor genotype by polymerase chain reaction and allele-specific oligonucleotide hybridization. Blood pressure values were lower in CC homozygotes than in heterozygotes and AA homozygotes; the difference was statistically significant for clinic measurements (mean difference for mean blood pressure, -6.6 mm Hg, P = .01; 95% confidence interval, -1.6 to -11.7 mm Hg) but not for ambulatory blood pressure measurements. CC homozygotes also presented a lower incidence of a positive family history of hypertension (P = .027). No statistically significant differences among AT1 receptor A/C1166 genotypes were observed for left ventricular mass or carotid artery wall thickness. We conclude that the present study does not support a major role of the AT1 receptor gene A/C1166 polymorphism as a marker of conditions associated with increased cardiovascular risk.

BACKGROUND:It has been reported that the D allele of an insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene is associated with conditions of increased cardiovascular risk, including left ventricular hypertrophy.METHODS AND RESULTS:Considering that a genetically determined overactivity of the renin-angiotensin system may influence cardiac as well as vascular growth, we investigated possible relations between ACE I/D genotype and carotid artery wall thickness (B-mode ultrasound) in 199 subjects, 50 to 64 years old, sampled from the general population of Vobarno, a small town in northern Italy. ACE DD genotype was associated with significantly higher common carotid artery intima-media thickness (P = .003). The occurrence of carotid atherosclerotic plaques was similar in the different genotypes. There was no association of the ACE I/D genotype with blood pressure values (either casual of 24-hour ambulatory monitored).CONCLUSIONS:ACE DD genotype may be considered a risk factor for the development of common carotid intima-media thickening in our study population.

We investigated the effects of chronic treatment with the angiotensin-converting enzyme (ACE) inhibitor fosinopril on cardiac and vascular noradrenergic neurotransmission as related to cardiovascular hypertrophy in spontaneously hypertensive rats (SHRs). SHRs were treated with fosinopril at "high dose" (SHR-HD, 25 mg/kg/day) or "low dose" (SHR-LD, 1 mg/kg/day) from the 6th to the 12th week of age, and compared to age-matched untreated SHRs (SHR-C) and Wistar-Kyoto controls (WKY). Blood pressure was significantly reduced in SHR-HD but not in SHR-LD when compared to SHR-C. The antihypertensive dose of fosinopril reduced both cardiac and vascular hypertrophy, whereas the low dose was effective only in reducing vascular hypertrophy. Several differences in presynaptic and postsynaptic cardiovascular noradrenergic neurotransmission were observed between SHR-C and WKY rats (increased cardiac norepinephrine concentration, down-regulation of cardiac beta-adrenoceptors, reduced alpha-adrenergic receptor-mediated vasoconstrictor response of small mesenteric arteries to exogenous norepinephrine). All these differences were abolished by ACE inhibitor treatment, both at antihypertensive or at subantihypertensive doses. The results of this study are consistent with the hypothesis that chronic ACE inhibition may exert an inhibitory modulation on the peripheral adrenergic transmission, which is not related to blood pressure reduction. This modulation does not appear to be a determinant in preventing the development of cardiac hypertrophy but may play a role in the regression of vascular structural alterations in spontaneously hypertensive rats.